2,5,7-triamino-4-phenyl (or thienyl)-pyrimido[4,5-d]pyrimidines



United States Patent 3,134,778 2,5,7-TRIAMINO-4-PHENYL (0R THIENYL)-PYRlMlD0[4,5-d]PYRIMIDINES Joseph Weinstock, Phoenixville, and Virgil D.Wlebelhaus, Springfield, Pa., assignors to Smith Kline & FrenchLaboratories, Philadelphia, Pa., a corporation of Pennsylvania NoDrawing. Continuation of application Ser. No. 142,474, Oct. 3, 1961.This application Aug. 20, 1963, Ser. No. 303,424

4 Claims. (Cl. 260256.4)

This invention relates to substituted pyrimido[4,5-d] pyrimidines. Morespecifically this invention relates to tetrasubstituted pyrimido[4,5-d]pyrimidines having useful diuretic and hypotensive activity.

The novel compounds of this invention are represented by the followingstructural formula:

' I R R N R 1 when:

R and R represent hydrogen, lower alkyl or phenyl lower alkyl; and

R represents aryl or substituted aryl, such as for example phenyl orchloro, methyl, methoxy, trifiuoromethyl, hydroxy, or amino substitutedphenyl, or a 5- to 6-membered heterocyclic group having a minimum of twoand a maximum of eight carbon atoms and a minimum of one hetero atomsuch as oxygen, sulfur or nitrogen, the heterocyclic group being forexample thienyl, furyl, pyrrolyl, pyridyl, pyrazolyl, thiazolyl,imidazolyl, isoxazolyl or thianaphthenyl. 7

By the term lower alkyl where used herein alone or in combination withother terms, aliphatic groups having from one to four carbon atoms areindicated.

An advantageous group of compounds of this invention is represented byFormula I when:

R and R represent hydrogen or methyl; and

R represents phenyl or thienyl.

A particularly active diuretic compound is2,5,7-triamino-4-phenylpyrimido [4,5 -d] pyrimidine.

Also included in this invention are the nontoxic, pharmaceuticallyacceptable acid addition salts of the free bases described above. Thesesalts are readily obtained from the free bases by treatment with a wideselection of inorganic and organic acids. Exemplary of such acids arehydrochloric, hydrobromic, sulfuric, acetic, benzoic, citric, maleic,tartaric and the like. The compounds occur in some cases in a hydratedform.

Compounds of this invention are prepared by reacting a5-cyano-6-aminopyrimidine having the following formula:

N rim-f 1 l NRrRi E II ethanol and in the presence of an alkali metalalkoxide, for example sodium or potassium methoxide or ethoxide. Thereaction temperature is preferably the reflux temperature of thereaction mixture in the range of from 8() 140 C., and the reaction timeis variable, usually for from 24 to 60 hours. Essentially equivalentamounts of the reactants are employed.

The. 5-cyano-6-aminopyrimidines of Formula II are either known or areconveniently prepared by the condensation of an amidine or guanidinewith malonitrile or an alkoxymethylenemalonitrile. The pyrimidineintermediates having a Z-monosubstituted amino substituent areadvantageously prepared from a 2-alkylthio derivative by reaction withthe appropriate monosubstituted amine, the 2-alkylthio derivatives beingprepared by the condensation of thiourea with analkoxymethylenemalonitrile or l-amino-l-chloro-2,Z-dicyanoethylenefollowed by alkylation of the Z-mercapto group.

Of course, alternatively the 2-alkylthiopyrimidine intermediates can beused directly in the above described condensation with a guanidine andthen the resulting 2-alkylthiopyrimido [4,5-d1pyrimid-ine is reactedwith the appropriate monoor disubstituted amine to give the 2-monoordisubstituted amino pyrimido[4,5-d]pyrimid-ine.

The compounds of this invention as represented by Formula I areadvantageously used in admixture with a pharmaceutical carrier in dosageunits comprising from about 10 to about mg. of active compound perdosage unit. Administration of said dosage unit for from 1 to 6 timesdaily produces useful diuretic and hypotensive activity.

Of course, variations of the synthetic schemes described above for thepreparation of the compounds of this invention are within the skill ofthose in the art. The following examples illustrate the perparation ofcompounds of this invention.

Example 1 To a solution of 12.0 g. of sodium methoxide in 600 ml. ofCellosolve is added 21.1 g. of 2,6-diamino-4-phenyl-5- cyanopyrimidineand 18.2 g. of guanidine carbonate. The resulting mixture is heated atreflux for 48 hours and then cooled. The precipitated solid is removedby filtration, washed with a large volume of water and dried in vacuo at70 C. to give 2,5,7-triamino-4-phenylpyrimido[4,5-d] pyrimidine, M.P.300 C. The white product is recrystallised from 5 N hydrochloric acid,then from water to give 2,5,7-triamino 4 phenylpyrimido[4,5-d]pyrimidinemonohydrochloride, monohydrate, M.P. 300 C.

Example 2 Following the general procedure described in Ber. 91, 1824,1830 (1958), 2-thiopheneglyoxy1onitrile is condensed with malononitrilein the presence of an ammonium salt to give Z-thienoylrnalonitrile whichis then reacted with dirnethylsulfate in the presence of sodiumbicarbonate to give 1-(2-thienyl)-1-rnethoxy-2,Z-dicyanoethylene. Thelatter compound is then condensed with guanidine to yield 2,6-diamino-4-(Z-thienyl) -5-cyanopyrimidine.

Following the procedure of Example 1, a mixture of 12 g. of sodiummethoxide, 21.7 g. of 2,6-diamino-4-(2- thienyl)-5-cyanopyrimidine and18.2 g. of guanidine carbonate in 500 ml. of Cellosolve is refluxed for48 hours. The reaction mixture is cooled and filtered to isolate thesolid 2,5,7-triamino 4 (2 thienyl)-pyrimido[4,5-d]pyrimidine.

Example 3 Following the procedure of Ber. 91, 1830 (1958), 1-methoxy-1-phenyl-2,2-dicyanoethylene is condensed withN,N-dimethylguanidine to give 2-dimethylamino-4-phenyl-5-cyano-6-aminopyrimidine.

To a solution of 6.0 g. of sodium methoxide in 300 ml. of Cellosolve isadded 11.4 g. of 2-dimethylamino-4-phenyl- -cyano-6-aminopyrimidine and9.1 g. of guanidine car bonate. The mixture is refluxed for 48 hours andWorked up as described in Eample 1 to yield 2-dimethylamino-4- phenyl-5,7-diaminopyrimido [4,5 -d] pyrimidine.

Example 4 To a solution of 18 g. of sodium methoxide in 750 ml. ofCellosolve is added 30.0 g. of 4-phenyl-2,6-diamino-5- cyanopyrimidineand 31.0 g. of N,N-dimethyl-guanidine carbonate. The resulting mixtureis heated at reflux for 48 hours and worked up as in Example 1 to give4-pher1yl- 2,5-diamino-7-dimethylaminopyrimido[4,5-d]pyrimidine.

Example 5 To a solution of 5.0 g. of sodium in 200 m1. of absoluteethanol is added 15.2 g. of thiourea and the mixture is warmed to affectsolution. The solution is cooled to 40 C. and 34.6 g. ofl-methoxy-1-phenyl-2,2-dicyanoethylene is added portion-wise. Themixture is heated on the steam bath for one hour and then cooled to givethe sodium salt of 2-mercapto-4-phenyl-5-cyano-6-aminopyrimidine whichis dissolved in water and treated with an excess of methyl iodide toyield 2-n1ethylthio-4-phenyl-5-cyano-6-aminopyr-imidine.

Following the procedure of Example 1, equimolar amounts of sodiummethoxide, 2-methylthio-4-phenyl-5- cyano-fi-aminopyriniidine andguanidine carbonate are reacted to give after similar Workup2-methylthio-4-phenyl- 5,7-diamino-pyrimido[4,5-d] pyrimidine. Thelatter is heated in an alcohol solution with an excess of 25% aqueousmethylamine in an autoclave at 130 C. for three hours to yieldZ-methyl-amino-4-phenyl-5,7-diaminopyrimido [4,5-d]pyrimidine.

This application is a continuation of Serial No. 142,474, filed October3, 1961, and now abandoned.

4 What is claimed is: 1. A chemical compound selected from the groupconsisting of a free base of the following formula:

N N 11.1% I NH.

zN K 3. 2,5,7-triamino 4 phenylpyrimido [4,S-dJpyrimidine hydrochloride.

4. A chemical compound of the following formula:

No references cited.

1. A CHEMICAL COMPOUND SELECTED FROM THE GROUP CONSISTING OF A FREE BASEOF THE FOLLOWING FORMULA: